Estimation of ascertainment bias and its effect on power in clinical trials with time-to-event outcomes

While the gold standard for clinical trials is to blind all parties -- participants, researchers, and evaluators -- to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of post-randomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this manuscript, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial versus changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed.Comment: 31 pages, 11 figures; submitted to Statistics in Medicin

Patterns, Predictors, and Outcomes of Falls Trajectories in Older Adults: The MOBILIZE Boston Study with 5 Years of Follow-Up

Background: Falls may occur as unpredictable events or in patterns indicative of potentially modifiable risks and predictive of adverse outcomes. Knowing the patterns, risks, and outcomes of falls trajectories may help clinicians plan appropriate preventive measures. We hypothesized that clinically distinct trajectories of falls progression, baseline predictors and their coincident clinical outcomes could be identified. Methods: We studied 765 community-dwelling participants in the MOBILIZE Boston Study, who were aged 70 and older and followed prospectively for falls over 5 years. Baseline demographic and clinical data were collected by questionnaire and a comprehensive clinic examination. Falls, injuries, and hospitalizations were recorded prospectively on daily calendars. Group-Based Trajectory Modeling (GBTM) was used to identify trajectories. Results: We identified 4 distinct trajectories: No Falls (30.1%), Cluster Falls (46.1%), Increasing Falls (5.8%) and Chronic Recurring Falls (18.0%). Predictors of Cluster Falls were faster gait speed (OR 1.69 (95CI, 1.50–2.56)) and fall in the past year (OR 3.52 (95CI, 2.16–6.34)). Predictors of Increasing Falls were Diabetes Mellitus (OR 4.3 (95CI, 1.4–13.3)) and Cognitive Impairment (OR 2.82 (95CI, 1.34–5.82)). Predictors of Chronic Recurring Falls were multi-morbidity (OR 2.24 (95CI, 1.60–3.16)) and fall in the past year (OR 3.82 (95CI, 2.34–6.23)). Symptoms of depression were predictive of all falls trajectories. In the Chronic Recurring Falls trajectory group the incidence rate of Hospital visits was 121 (95% CI 63–169) per 1,000 person-years; Injurious falls 172 (95% CI 111–237) per 1,000 person-years and Fractures 41 (95% CI 9–78) per 1,000 person-years. Conclusions: Falls may occur in clusters over discrete intervals in time, or as chronically increasing or recurring events that have a relatively greater risk of adverse outcomes. Patients with multiple falls, multimorbidity, and depressive symptoms should be targeted for preventive measures

Increased bone mineral density in Aboriginal and Torres Strait Islander Australians: Impact of body composition differences

Bone mineral density (BMD) has been reported to be both higher and lower in Indigenous women from different populations. Body composition data have been reported for Indigenous Australians, but there are few published BMD data in this population. We assessed BMD in 161 Indigenous Australians, identified as Aboriginal (n = 70), Torres Strait Islander (n = 68) or both (n = 23). BMD measurements were made on Norland-XR46 (n = 107) and Hologic (n = 90) dual-energy X-ray absorptiometry (DXA) machines. Norland BMD and body composition measurements in these individuals, and also in 36 Caucasian Australians, were converted to equivalent Hologic BMD (BMDH) and body composition measurements for comparison

Clinical Meaningfulness of the Changes in Muscle Performance and Physical Function Associated With Testosterone Administration in Older Men With Mobility Limitation

Context. Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. Methods. Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. Results. Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. Conclusions. Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this populatio

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.Objective: To investigate the genetic regulation of serum E2 and E1 in men.Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1

Interactions between sleep, stress, and metabolism: From physiological to pathological conditions

AbstractPoor sleep quality due to sleep disorders and sleep loss is highly prevalent in the modern society. Underlying mechanisms show that stress is involved in the relationship between sleep and metabolism through hypothalamic–pituitary–adrenal (HPA) axis activation. Sleep deprivation and sleep disorders are associated with maladaptive changes in the HPA axis, leading to neuroendocrine dysregulation. Excess of glucocorticoids increase glucose and insulin and decrease adiponectin levels. Thus, this review provides overall view of the relationship between sleep, stress, and metabolism from basic physiology to pathological conditions, highlighting effective treatments for metabolic disturbances

The Method of Randomization for Cluster-Randomized Trials: Challenges of Including Patients with Multiple Chronic Conditions

Cluster-randomized clinical trials (CRT) are trials in which the unit of randomization is not a participant but a group (e.g. healthcare systems or community centers). They are suitable when the intervention applies naturally to the cluster (e.g. healthcare policy); when lack of independence among participants may occur (e.g. nursing home hygiene); or when it is most ethical to apply an intervention to all within a group (e.g. school-level immunization). Because participants in the same cluster receive the same intervention, CRT may approximate clinical practice, and may produce generalizable findings. However, when not properly designed or interpreted, CRT may induce biased results. CRT designs have features that add complexity to statistical estimation and inference. Chief among these is the cluster-level correlation in response measurements induced by the randomization. A critical consideration is the experimental unit of inference; often it is desirable to consider intervention effects at the level of the individual rather than the cluster. Finally, given that the number of clusters available may be limited, simple forms of randomization may not achieve balance between intervention and control arms at either the cluster- or participant-level. In non-clustered clinical trials, balance of key factors may be easier to achieve because the sample can be homogenous by exclusion of participants with multiple chronic conditions (MCC). CRTs, which are often pragmatic, may eschew such restrictions. Failure to account for imbalance may induce bias and reducing validity. This article focuses on the complexities of randomization in the design of CRTs, such as the inclusion of patients with MCC, and imbalances in covariate factors across clusters

Self-Reported Head Trauma Predicts Poor Dual Task Gait in Retired National Football League Players

Symptomatic head trauma associated with American-style football (ASF) has been linked to brain pathology, along with physical and mental distress in later life. However, the longer-term effects of such trauma on objective metrics of cognitive-motor function remain poorly understood. We hypothesized that ASF-related symptomatic head trauma would predict worse gait performance, particularly during dual task conditions (ie, walking while performing an additional cognitive task), in later life. Sixty-six retired professional ASF players aged 29 to 75 years completed a health and wellness questionnaire. They also completed a validated smartphone-based assessment in their own homes, during which gait was monitored while they walked normally and while they performed a verbalized serial-subtraction cognitive task. Participants who reported more symptomatic head trauma, defined as the total number of impacts to the head or neck followed by concussion-related symptoms, exhibited greater dual task cost (ie, percentage increase) to stride time variability (ie, the coefficient of variation of mean stride time). Those who reported ≥1 hit followed by loss of consciousness, compared to those who did not, also exhibited greater dual task costs to this metric. Relationships between reported trauma and dual task costs were independent of age, body mass index, National Football League career duration, and history of musculoskeletal surgery. Symptomatic head trauma was not correlated with average stride times in either walking condition. Remote, smartphone-based assessments of dual task walking may be utilized to capture meaningful data sensitive to the long-term impact of symptomatic head trauma in former professional ASF players and other contact sport athletes. ANN NEUROL 2020;87:75-8